The insulin-like growth factor-I receptor (IGF-IR), like the insulin receptor, is a tyrosine kinase transmembrane glycoprotein. Expression of the IGF-IR is highly regulated during development and in certain disease states including diabetes and cancer. The activity of the IGF-IR promoter is regulated by various growth factors and nuclear transcription actors. Whereas, IGF-I inhibits the expression of its own receptor, fibroblast growth factor (FGF) enhances expression via a mechanism which involves enhancement of the promoter. Tumor suppressor gene products, including WT- 1 and p53, inhibit the promoter activity of the IGF-IR. Mutant tumor suppressors, on the other hand, lost their ability to suppress the IGF-lR promoter. These results may explain the increased levels of IGF-I receptors in many cancers expressing mutant forms of these tumor suppressor gene products. Mutational analysis of the IGF-IR has shed light on the structural and functional aspects of this tyrosine kinase receptor. Mutation of the tyrosine kinase domain results in loss of all IGF-I-induced functions including the ability of this receptor to induce tumors in nude mice. Deletion of the C-terminus region of the receptor, though resulting in a moderate decrease in IGF-I-induced functions such as mitogenesis, results in a loss in tumorigenicity. Substitution of the double tyrosines (1250, 1251) in the C-terminus similarly inhibits tumorigenesis. Thus, the ability of the IGF-IR to induce tumors seems to emanate, at least partially, from the C-terminal region of the receptor beta subunit.